Professional Information — Pindolol Pindolol 5 Mg

Indications and Usage

Pindolol tablets are indicated in the management of hypertension. It may be used alone or concomitantly with other antihypertensive agents, particularly with a thiazide-type diuretic.

Dosage and Administration

The dosage of pindolol tablets should be individualized. The recommended initial dose of pindolol tablets is 5 mg b.i.d. alone or in combination with other antihypertensive agents. An antihypertensive response usually occurs within the first week of treatment. Maximal response, however, may take as long as or occasionally longer than 2 weeks. If a satisfactory reduction in blood pressure does not occur within 3 to 4 weeks, the dose may be adjusted in increments of 10 mg/day at these intervals up to a maximum of 60 mg/day.

Contraindications

Pindolol tablets are contraindicated in: 1) bronchial asthma; 2) overt cardiac failure; 3) cardiogenic shock; 4) second and third degree heart block; 5) severe bradycardia. (See WARNINGS.)

Adverse Reactions

Most adverse reactions have been mild. The incidences listed in the following table are derived from 12-week comparative double-blind, parallel design trials in hypertensive patients given pindolol as monotherapy, given various active control drugs as monotherapy, or given placebo. Data for pindolol and the positive controls were pooled from several trials because no striking differences were seen in the individual studies, with one exception. When considering all adverse reactions reported, the frequency of edema was noticeably higher in positive control trials (16% pindolol vs. 9% positive control) than in placebo controlled trials (6% pindolol vs. 3% placebo). The table includes adverse reactions either volunteered or elicited, and at least possibly drug-related, which were reported in greater than 2% of pindolol patients and other selected important reactions.

The following selected (potentially important) adverse reactions were seen in 2% or fewer patients and their relationship to pindolol is uncertain. CENTRAL NERVOUS SYSTEM: anxiety, lethargy; AUTONOMIC NERVOUS SYSTEM: visual disturbances, hyperhidrosis; CARDIOVASCULAR: bradycardia, claudication, cold extremities, heart block, hypotension, syncope, tachycardia, weight gain; GASTROINTESTINAL: diarrhea, vomiting; RESPIRATORY: wheezing; UROGENITAL: impotence, pollakiuria; MISCELLANEOUS: eye discomfort or burning eyes.

Drug Interactions

Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blocking agents. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or postural hypotension.

Pindolol has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions.

Pindolol has been shown to increase serum thioridazine levels when both drugs are coadministered. Pindolol levels may also be increased with this combination.

Risk of Anaphylactic Reaction

While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Overdosage

No specific information on emergency treatment of overdosage is available. Therefore, on the basis of the pharmacologic actions of pindolol, the following general measures should be employed as appropriate in addition to gastric lavage:

Excessive Bradycardia:administer atropine; if there is no response to vagal blockade, administer isoproterenol cautiously.

Cardiac Failure:digitalize the patient and/or administer diuretic. It has been reported that glucagon may be useful in this situation.

Hypotension:administer vasopressors, e.g., epinephrine or norepinephrine, with serial monitoring of blood pressure. (There is evidence that epinephrine may be the drug of choice.)

Bronchospasm:administer a beta ₂stimulating agent such as isoproterenol and/or a theophylline derivative.

A case of an acute overdosage has been reported with an intake of 500 mg of pindolol by a hypertensive patient. Blood pressure increased and heart rate was ≥ 80 beats/min. Recovery was uneventful. In another case, 250 mg of pindolol was taken with 150 mg diazepam and 50 mg nitrazepam, producing coma and hypotension. The patient recovered in 24 hours.

Description

Pindolol, a synthetic beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity is 1-(Indol-4-yloxy)-3-(isopropylamino)-2-propanol.

Pindolol, USP is a white to off-white, crystalline powder having a faint odor which is practically insoluble in water; slightly soluble in methanol; and very slightly soluble in chloroform.

Each tablet for oral administration contains pindolol and the following inactive ingredients: crospovidone, lactose, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

Clinical Pharmacology

Pindolol is a nonselective beta-adrenergic antagonist (beta-blocker) which possesses intrinsic sympathomimetic activity (ISA) in therapeutic dosage ranges but does not possess quinidine-like membrane stabilizing activity.

PHARMACODYNAMICS

In standard pharmacologic tests in man and animals, pindolol attenuates increases in heart rate, systolic blood pressure, and cardiac output resulting from exercise and isoproterenol administration, thus confirming its beta-blocking properties. The ISA or partial agonist activity of pindolol is mediated directly at the adrenergic receptor sites and may be blocked by other beta-blockers. In catecholamine depleted animal experiments, ISA is manifested as an increase in the inotropic and chronotropic activity of the myocardium. In man, ISA is manifested by a smaller reduction in the resting heart rate (4 to 8 beats/min) than is seen with drugs lacking ISA. There is also a smaller reduction in resting cardiac output. The clinical significance of this observation has not been evaluated and there is no evidence, or reason to believe, that exercise cardiac output is less affected by pindolol.

Pindolol has been shown in controlled, double-blind clinical studies to be an effective antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics. Divided dosages in the range of 10 mg to 60 mg daily have been shown to be effective. As monotherapy, pindolol is as effective as propranolol, α-methyldopa, hydrochlorothiazide, and chlorthalidone in reducing systolic and diastolic blood pressure. The effect on blood pressure is not orthostatic, i.e., pindolol was equally effective in reducing the supine and standing blood pressure.

In open, long-term studies up to 4 years, no evidence of diminution of the blood pressure lowering response was observed.

An average 3-pound increase in body weight has been noted in patients treated with pindolol alone, a larger increase than was observed with propranolol or placebo. The weight gain appeared unrelated to blood pressure response and was not associated with an increased risk of heart failure, although edema was more common than in control patients. Pindolol does not have a consistent effect on plasma renin activity.

The mechanism of the antihypertensive effects of beta-blocking agents has not been established, but several mechanisms have been postulated: 1) an effect on the central nervous system resulting in a reduced sympathetic outflow to the periphery, 2) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic receptor sites, leading to decreased cardiac output, 3) an inhibition of renin release. These mechanisms appear less likely for pindolol than other beta-blockers in view of the modest effect on resting cardiac output and renin.

Beta-blockade therapy is useful when it is necessary to suppress the effects of beta-adrenergic agonists in order to achieve therapeutic goals. However, in certain clinical situations, (e.g., cardiac failure, heart block, bronchospasm), the preservation of an adequate sympathetic tone may be necessary to maintain vital functions. Although a beta-antagonist with ISA such as pindolol does not eliminate sympathetic tone entirely, there is no controlled evidence that it is safer than other beta-blockers in such conditions as heart failure, heart block, or bronchospasm or is less likely to cause those conditions. In single-dose studies of the effects of beta-blockers on FEV ₁, pindolol was indistinguishable from other non-cardioselective agents in its reduction of FEV ₁, and its reduction in the effectiveness of an exogenous beta-agonist.

Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.

PHARMACOKINETICS AND METABOLISM

Pindolol is rapidly and reproducibly absorbed (greater than 95%), achieving peak plasma concentrations within 1 hour of drug administration. Pindolol has no significant first-pass effect. The blood concentrations are proportional in a linear manner to the administered dose in the range of 5 mg to 20 mg. Upon repeated administration to the same subject, variation is minimal. After a single dose, intersubject variation for peak plasma concentrations was about 4-fold (e.g., 45 to 167 ng/mL for a 20 mg dose). Upon multiple dosing, intersubject variation decreased to 2- to 2.5-fold. Pindolol is only 40% bound to plasma proteins and is evenly distributed between plasma and red cells. The volume of distribution in healthy subjects is about 2 L/kg.

Pindolol undergoes extensive metabolism in animals and man. In man, 35% to 40% is excreted unchanged in the urine and 60% to 65% is metabolized primarily to hydroxy-metabolites which are excreted as glucuronides and ethereal sulfates. The polar metabolites are excreted with a half-life of approximately 8 hours and thus multiple dosing therapy (q.8H) results in a less than 50% accumulation in plasma. About 6% to 9% of an administered intravenous dose is excreted by the bile into the feces.

The disposition of pindolol after oral administration is monophasic with a half-life in healthy subjects or hypertensive patients with normal renal function of approximately 3 to 4 hours. Following t.i.d. administration (q.8H), no significant accumulation of pindolol is observed.

In elderly hypertensive patients with normal renal function, the half-life of pindolol is more variable, averaging about 7 hours, but with values as high as 15 hours.

In hypertensive patients with renal diseases, the half-life is within the range expected for healthy subjects. However, a significant decrease (50%) in volume of distribution (V _D) is observed in uremic patients and V _Dappears to be directly correlated to creatinine clearance. Therefore, renal drug clearance is significantly reduced in uremic patients, resulting in a significant decrease in urinary excretion of unchanged drug. Uremic patients with a creatinine clearance of less than 20 mL/min generally excreted less than 15% of the administered dose unchanged in the urine.

In patients with histologically diagnosed cirrhosis of the liver, the elimination of pindolol was more variable in rate and generally significantly slower than in healthy subjects. The total body clearance of pindolol in cirrhotic patients ranged from about 50 to 300 mL/min and was directly correlated to antipyrine clearance. The half-life ranges from 2.5 hours to greater than 30 hours. These findings strongly suggest that caution should be exercised in dosage adjustments of pindolol in such patients.

The bioavailability of pindolol is not significantly affected by coadministration of food, hydralazine, hydrochlorothiazide or aspirin. Pindolol has no effect on warfarin activity or the clinical effectiveness of digoxin, although small transient decreases in plasma digoxin concentrations were noted.

How Supplied / Storage and Handling

Pindolol Tablets, USP are available as 5 mg and 10 mg tablets.

The 5 mg tablets are round white tablets, debossed "MP 178" bisected on one side and blank on the other side.

The 10 mg tablets are round white tablets, debossed "MP 183" bisected on one side and blank on the other side.

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature]

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Patient Counseling Information

Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of pindolol therapy without the physician's advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult the physician at the first sign or symptom of impending failure.